Compound (I) is an endothelin antagonist. The endothelins are a family of endogenous 21 amino acid peptides comprising three isoforms, endothelin-1 (ET-1), endothelin-2 and endothelin-3. The endothelins are formed by cleavage of the Trp21-Val22 bond of their corresponding proendothelins by an endothelin converting enzyme. The endothelins are among the most potent vasoconstrictors known and have a characteristic long duration of action. They exhibit a wide range of other activities including cell proliferation and mitogenesis, extravasation and chemotaxis, and also interact with a number of other vasoactive agents.
The endothelins are released from a range of tissue and cell sources including vascular endothelium, vascular smooth muscle, kidney, liver, uterus, airways, intestine and leukocytes. Release can be stimulated by hypoxia, shear stress, physical injury and a wide range of hormones and cytokines. Elevated endothelin levels have been found in a number of disease states in man including cancers.
Recently, endothelin A receptor antagonists have been identified as potentially of value in the treatment of cancer (Cancer Research, 56, 663-668, Feb. 15, 1996 and Nature Medicine, Volume 1, Number 9, September 1999, 944-949).
Cancer affects an estimated 10 million people worldwide. This figure includes incidence, prevalence and mortality. More than 4.4 million cancer cases are reported from Asia, including 2.5 million cases from Eastern Asia, which has the highest rate of incidence in the world. By comparison, Europe has 2.8 million cases, North America 1.4 million cases, and Africa 627,000 cases.
In the UK and US, for example, more than one in three people will develop cancer at some point in their life. Cancer mortality in the U.S. is estimated to account for about 600,000 a year, about one in every four deaths, second only to heart disease in percent of all deaths, and second to accidents as a cause of death of children 1-14 years of age. The estimated cancer incidence in the U.S. is now about 1,380,000 new cases annually, exclusive of about 900,000 cases of non-melanotic (basal and squamous cell) skin cancer.
Cancer is also a major cause of morbidity in the UK with nearly 260,000 new cases (excluding non-melanoma skin cancer) registered in 1997. Cancer is a disease that affects mainly older people, with 65% of cases occurring in those over 65. Since the average life expectancy in the UK has almost doubled since the mid nineteenth century, the population at risk of cancer has grown. Death rates from other causes of death, such as heart disease, have fallen in recent years while deaths from cancer have remained relatively stable. The result is that 1 in 3 people will be diagnosed with cancer during their lifetime and 1 in 4 people will die from cancer. In people under the age of 75, deaths from cancer outnumber deaths from diseases of the circulatory system, including ischaemic heart disease and stroke. In 2000, there were 151,200 deaths from cancer. Over one fifth (22 per cent) of these were from lung cancer, and a quarter (26 per cent) from cancers of the large bowel, breast and prostate.
Worldwide, the incidence and mortality rates of certain types of cancer (of stomach, breast, prostate, skin, and so on) have wide geographical differences which are attributed to racial, cultural, and especially environmental influences. There are over 200 different types of cancer but the four major types, lung, breast, prostate and colorectal, account for over half of all cases diagnosed in the UK and US. Prostate cancer is the fourth most common malignancy among men worldwide, with an estimated 400,000 new cases diagnosed annually, accounting for 3.9 percent of all new cancer cases.
Current options for treating cancers include surgical resection, external beam radiation therapy and/or systemic chemotherapy. These are partially successful in some forms of cancer, but are not successful in others. There is a clear need for new therapeutic treatments.
Compound (I) is exemplified and described in WO96/40681 as Example 36. WO96/40681 claims the endothelin receptors described therein for the treatment of cardiovascular diseases. The use of Compound (I) in the treatment of cancers and pain is described in WO04/018044.
Compound (I) has the following structure:
and is also known as zibotentan.
In WO04/018044 an endothelin human receptor binding assay is described. The pIC50 (negative log of the concentration of compound required to displace 50% of the ligand) for Compound (I) at the ETA receptor was 8.27 [8.23-8.32] (n=4). Compound (I) is thus an excellent endothelin antagonist.
WO96/40681 discloses in general terms, certain pharmaceutically compositions that may be used to formulate compounds of the invention described therein (for example see Example 71).
WO04/018044 describes a lactose formulation of Compound (I):                Compound (I);        Lactose monohydrate (filler);        Croscarmellose sodium (disintegrant);        Povidone (binder);        Magnesium stearate (lubricant);        Hypromellose (film coat component);        Polyethylene glycol 300 (film coat component); and        Titanium dioxide (film coat component).        
This tablet formulation, based on a lactose monohydrate filler and with a white film coat, was developed for use in Phase I and II clinical studies, but proved unsuitable for use in late-stage development because:                the tablets were prone to capping and edge-damage;        the active ingredient was subject to hydrolytic degradation;        the active ingredient was subject to degradation on exposure to light; and        strict controls must be applied to lactose monohydrate to minimize the risk of TSE (Transmissible Spongiform Encephalopathy) transmission, as described in EMEA/410/01 Rev. 2 Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products, (Adopted by CPMP/CVMP October 2003).        
The term ‘capping’ means the complete or partial separation of a saucer-shaped disc from the top or bottom surface of a tablet during compression of the material to form a tablet or during subsequent processes and/or handling. Capping is described in Carstensen, J. T., Solid pharmaceutics: mechanical properties and rate phenomena, Academic press, New York (1980) and in Sheth et al., Pharmaceutical dosage forms: Tablets. Vol 1. Ed Liebermann and Lachmann, Pub. Marcel Dekker, New York (1980).
The term ‘edge damage’ means loss of material from the regions where the tablet surfaces intersect, during compression of the material to form a tablet or during subsequent processes and/or handling.
Compound (I) is subject to hydrolytic degradation at low and high pH, the principal degradation product being Compound (I) formyl hydrazide:

Over time, Compound (I) formyl hydrazide may further degrade to form Compound (I) hydrazide:

Compound (I) formyl hydrazide and Compound (I) hydrazide are also formed under hydrolytic conditions upon exposure to light. In the solid state, the principal degradation product following exposure to light is Compound (I) des pyrazine:

In one aspect there is provided Compound (I) formyl hydrazide.
In one aspect there is provided Compound (I) hydrazide.
In one aspect there is provided Compound (I) des pyrazine.
In addition to the above, tablets need to possess sufficient hardness or sufficient mechanical strength, which will prevent a compact from becoming damaged during subsequent processing or transport. This is related to the size of the tablet and when measured in kiloponds (kp) is typically <15 kp. Suitably an immediate release tablet has a hardness in the range of from 5 to 20 kp, for example about 10 kp.
Friability is the phenomenon whereby tablet surfaces are damaged and/or show evidence of cracking or breakage when subjected to mechanical agitation (e.g. during processing, handling or transportation).
Disintegration is the process whereby a tablet breaks down into its constituent particles when in contact with a fluid. Disintegration is a desirable property for an immediate release tablet as this leads to an increase in surface area and hence may lead to an increased rate of dissolution. In vivo, disintegration should occur as soon as possible following administration to the gastrointestinal tract, for example within 15 minutes. For immediate release tablets a suitable disintegration time under the standard United States Pharmacopoeia (USP) disintegration method is in the range of for example about 3 to 15 minutes and typically 5 to 8 minutes. Generally in the in-vivo setting immediate release tablets are not designed to exhibit significant disintegration in the oral cavity. Rather the disintegration occurs in the upper GI tract, predominantly in the stomach. An immediate release tablet formulation may include a disintegrant in order to promote tablet disintegration.
Immediate release allows the drug to dissolve in the gastrointestinal contents, with no intention of delaying or prolonging the dissolution or absorption of the drug (ICH Guideline Q6A: “Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances” Published in the Federal Register, Dec. 29, 2000, Volume 65, Number 251, Notices, Page 83041-83063).
Dissolution is the process whereby the active substance is released from a tablet following exposure to a fluid, such that the drug becomes dissolved in the fluid. For testing purposes the fluid is usually chosen to simulate conditions within the gastrointestinal tract, and is most usually an aqueous medium at low or neutral pH. For an immediate release tablet dissolution should be rapid, for example should be substantially complete within a period of 45 minutes following exposure to fluid under standard test conditions. For example, dissolution measured according to the general procedure of the USP using Apparatus 2 with 900 mL of 0.1 M Phosphate buffer at pH 7.8 as dissolution medium and a stirrer speed of 50 rpm. Typical USP acceptance criteria for dissolution from an immediate release tablet for the amount of active ingredient dissolved is typically 75 to 80% by weight of the active ingredient in the tablet. Tablet hardness, disintegration time and dissolution rate may be inter-related in that an increase in hardness may lead to an increase in disintegration time and hence a decrease in dissolution rate. The target profile for an immediate release tablet is one with sufficient hardness to prevent friability problems, but which disintegrates and dissolves rapidly within the gastrointestinal tract. An assessment of suitability may commence with the determination of tablet hardness followed, when appropriate, by more complex tests including disintegration testing and/or dissolution testing.
In an attempt to resolve the issues with the lactose formulation containing Compound (I) described above, alternative fillers for a composition comprising a Compound (I) were investigated. Acceptable results gave maximum total impurities <1.5% and minimum dissolution of 80% for dissolution (as described in the Experimental Section herein below) over 45 minutes.
Tablet cores prepared comprising Compound (I) with calcium phosphate dihydrate (as defined in the European Pharmacopia (PhEur)) (Calipharm™ D) as the filler were particularly poor with regard to dissolution performance. Similarly the use of magnesium carbonate, heavy (as defined in the PhEur) as the filler led to tablet cores which performed poorly with regard to impurity levels.
Microcrystalline cellulose is hygroscopic (see for example: ‘Equilibrium moisture content of pharmaceutical excipients’ Callahan, J. C., Cleary, G. W., Elefant, M., et al, Drug Dev Ind Pharm 1982; 8: 355-369) and moisture pick-up on storage of tablets using that as the filler (leading to hydrolytic degradation of Compound (I)) was expected. However, surprisingly, we have found that certain tablet compositions containing microcrystalline cellulose as one of the excipients do not result in any undue hydrolytic degradation of Compound (I). Tablet cores comprising Compound (I) with microcrystalline cellulose as the filler together with certain other excipients did not exhibit significant capping or edge damage, gave acceptable results with regard to dissolution performance, and did not exhibit significant chemical degradation when protected from light. Some degradation was observed following exposure to light, but the tablets in this study were not film coated.
Tablet cores prepared comprising Compound (I) with mannitol as the filler gave acceptable results in hardness experiments even though earlier prepared placebo tablet cores (no Compound (I)) with a mannitol-based formulation had showed that these tablet cores were subject to hardening on storage leading to increased disintegration times. These mannitol-based tablet cores were also acceptable with regard to dissolution performance; and although when stored at high temperature and humidity a deterioration in dissolution performance was observed for one of the formulations, this effect was thought to be attributable to the disintegrant and/or binder present in the formulation and was not considered significant with respect to the criteria used to assess dissolution performance.
Tablet cores with and without Compound (I) with both mannitol and microcrystalline cellulose as the fillers were acceptable with regard to both hardness over time and physical stability. Tablet cores containing Compound (I) with both mannitol and microcrystalline cellulose as the fillers also did not exhibit undue hydrolytic degradation despite the hygroscopic nature of microcrystalline cellulose, and were acceptable with regard to dissolution.
The formulations of Compound (I) comprising mannitol and/or microcrystalline cellulose have one or more advantageous properties selected from:                the formulation uses excipients which are not subject to strict controls to minimise the possibility of TSE transmission;        when the formulation is in the form of a tablet the formulation is physically stable in that it exhibits one or more of the following properties:                    it is not subject to significant capping/edge damage;            it shows a reduced tendency to harden on storage;            it does not absorb significant quantities of water on storage; and                        the formulation is chemically stable in that the levels of hydrolytic degradation of Compound (I) are low.        